The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China.
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
J Mol Endocrinol. 2020 Jan;64(1):43-52. doi: 10.1530/JME-19-0184.
Receptive endometrium is a prerequisite for successful embryo implantation, and it follows that poor endometrial receptivity is a leading cause of implantation failure. miRNAs play important roles as epigenetic regulators of endometrial receptivity and embryo implantation through post-transcriptional modifications. However, the mechanisms of action of many miRNAs are poorly understood. In this study, we investigated the role of the miR-183 family, comprising three miRNAs (miR-183-5p, miR-182-5p, and miR-96-5p) in endometrial receptivity and embryo implantation. The miR-183 family shows estrogen-dependent upregulation in endometrial Ishikawa (IK) cells. The miR-183 family also has a positive role in migration and proliferation of IK cells. Furthermore, JAr spheroid attachment experiments show that attachment rates were significantly decreased after treatment of IK cells with inhibitors for miR-183-5p and miR-182-5p and increased after treatment with miR-183-5p-mimic and miR-96-5p-mimic, respectively. The downstream analysis shows that catenin alpha 2 (CTNNA2) is a potential target gene for miR-183-5p, and this was confirmed in luciferase reporter assays. An in vivo mouse pregnancy model shows that inhibition of miR-183-5p significantly decreases embryo implantation rates and increases CTNNA2 expression. Downregulation of CTNNA2 in endometrial cells by miR-183-5p may be significant in mediating estrogenic effects on endometrial receptivity. In conclusion, miR-183-5p and the CTNNA2 gene may be potential biomarkers for endometrial receptivity and may be useful diagnostic and therapeutic targets for successful embryo implantation.
接受性子宫内膜是胚胎着床成功的前提，因此，子宫内膜容受性差是导致着床失败的主要原因。miRNA 通过转录后修饰作为子宫内膜容受性和胚胎着床的表观遗传调节剂发挥重要作用。然而，许多 miRNA 的作用机制仍知之甚少。在这项研究中，我们研究了 miR-183 家族在子宫内膜容受性和胚胎着床中的作用，该家族由三个 miRNA（miR-183-5p、miR-182-5p 和 miR-96-5p）组成。miR-183 家族在子宫内膜 Ishikawa（IK）细胞中表现出雌激素依赖性上调。miR-183 家族对 IK 细胞的迁移和增殖也有积极作用。此外，JAr 球体附着实验表明，IK 细胞用 miR-183-5p 和 miR-182-5p 抑制剂处理后附着率显著降低，而用 miR-183-5p 模拟物和 miR-96-5p 模拟物处理后附着率增加。下游分析表明，连环蛋白 alpha 2（CTNNA2）是 miR-183-5p 的潜在靶基因，这在荧光素酶报告基因实验中得到了证实。体内小鼠妊娠模型表明，抑制 miR-183-5p 显著降低胚胎着床率并增加 CTNNA2 表达。miR-183-5p 下调子宫内膜细胞中的 CTNNA2 可能在介导雌激素对子宫内膜容受性的影响方面具有重要意义。总之，miR-183-5p 和 CTNNA2 基因可能是子宫内膜容受性的潜在生物标志物，并且可能是成功胚胎着床的有用诊断和治疗靶点。
